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Matrix protein-mediated stem cell differentiation in vascular remodelling.

Description

Stem/progenitor cells are present in the vessel wall, and can differentiate into vascular lineages to participate in vascular remodelling in vivo. It is now widely accepted that vascular stem/progenitor cells can contribute to smooth muscle accumulation in the intima depending on the differential degrees of the vessel damage. However, the exact roles of vascular stem cells that may play during vascular remodelling are largely unknown.


Hypothesis: ECM proteins surrounding vascular stem cells are key elements in determining the fate of stem cells.


Objectives: To identify the effect of ECM proteins, e.g. hyaluronan and cartilage oligomeric matrix protein (COMP) in stem/progenitor differentiation into endothelial and smooth muscle cells. A pilot study demonstrated that hyaluronan or COMP can stimulate stem cell differentiation into vascular progenitor (Sca-1+/Lin-) phenotype. However, the underlying mechanism is still unclear.


Training: The ESR will perform a combination of coimmunoprecipitation, yeast two-hybrid, GST-pulldown, solid phase binding assays to characterize the interaction between hyaluronan or COMP and integrin α7ß1 or fibronectin. The ESR will apply two strategies to identify potential COMP binding partners. One is through yeast two-hybrid, the other is by use of immunoprecipitation and proteomics. The ESR will also perform high-throughput screening by both functional genomics and proteomics in stem/progenitor cells of wild-type and COMP-/- mice to explore potential mediators of COMP. The ESR will be trained in stem cell differentiation in vivo using matrix protein knockout mice, e.g. COMP. The Sca-1+ progenitor cells derived from ROSA26/ COMP-/- mice express the LacZ gene in all cells and SM-lacZ/COMP-/- mice in smooth muscle cells. These cells will be applied to the adventitial side of small vessel grafts in mice. The role of stem/progenitor cells will be monitored by cell tracing and the thickness of the vessel wall. The ESR will collaborate with UKH on standardization of protocols, and will include cultured vessels from HML in some of the studies.

Publications

Simpson, R.M., Hong, X., Wong, M.M., Karamariti, E., Bhaloo, S.I., Warren, D., Kong, W., Hu, Y., & Xu, Q. (2016). Hyaluronan is Crucial for Stem Cell Differentiation into Smooth Muscle Lineage. Stem Cells, 34, 1225-1238.

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Ph.D student / post-doc

Shirin Issa Bhaloo

Principal Investigator

Prof. Qingbo Xu